Nephrol Dial Transplant Vol. 20 No. 2 © ERA–EDTA 2005; all rights reserved
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Sir,
Toprak and Cirit propose that assessing volume status is essential to evaluating possible strategies for preventing contrast-induced nephropathy (CIN), since any condition associated with a reduction in circulating volume may be a potential risk factor for CIN. The authors also note the lack of volume status assessment in clinical studies of CIN. Clinical parameters of hydration are not always reliable. Acute renal failure induced by radiocontrast is a significant public-health problem. In this setting, current studies [1] and meta-analyses [2] have shown a potential preventive role of N-acetylcysteine (NAC). In support of these data, we described a strong NAC-induced suppression of oxidative stress-mediated proximal tubular injury, which represents a potential candidate mechanism for the prevention of CIN in humans [3]. Despite the omission of specific volume status assessment before angiography in our study, the patients involved presented quite similar laboratory and clinical conditions, including age (placebo group: 65.8 years; NAC group: 64.4 years), body mass index, hypertension, diabetes and heart failure. Only outpatients with a known history of mild-to-moderate chronic renal failure (CRF) and scheduled for angiography were included in the study. Exclusion criteria were conditions such as acute myocardial infarction, cardiogenic shock, renovascular hypertension, prior vasopressor use and unstable serum creatinine concentration (due to dehydration, for example) in repetitive measurements. In addition, ours was the first study in which diuretics were discontinued prior to angiography in order to avoid salt-water deprivation and possible interference with urine analysis of creatinine clearance, F2-isoprostanes, {a reliable marker of oxidative stress status in vivo [4] and 
-glutathione-S-transferase (a specific tubular proximal enzyme)} [5]. Specifically, 37% of placebo-group patients and 46% of NAC-group patients had experienced heart failure (P = NS). The left ventricular ejection fraction and symptomatic heart failure according to the New York Heart Association (NYHA) functional classes were similar and all patients received optimal treatment for heart failure. We recommended water ingestion by weight in control group patients and limited to 1000 ml per day in heart failure patients, according to current guidelines. All of these patients were designated NYHA functional class I and patients with normal function were in a steady-state status before the study.
In response to the questions asked by Toprak and Cirit, we reviewed the parameters serum creatinine, creatinine clearance, urinary fractional excretion of sodium, F2-isoprostanes and ventricular function in patients with heart failure. Both prior to and following radiocontrast administration, values were comparable between the placebo and NAC groups. Various meta-analyses of the role of NAC in the prevention of CIN have been published. In addition, it has been discussed in the literature that NAC could interfere with plasma creatinine measurement [6]. We have shown increased post-angiography mean creatinine clearance in the NAC group. However, we cannot be certain that our results were not affected by this NAC bias. Nevertheless, Shimizu et al. [7], using inulin clearance [the gold standard method to measure glomerular filtration rate (GFR)], demonstrated that NAC attenuates the GFR drop in 5/6-nephrectomized rats and concluded that, in the remnant kidney model, NAC has a protective effect. Therefore, we believe our present findings to be valid. In addition, it is well known that plasma and urinary excretion rates of the lipid peroxidation biomarker malondialdehyde are elevated in animal models and CRF patients [6,8]. In our study, elevated basal isoprostane levels support the hypothesis that the redox state plays an important role in renal fibrosis and progressive kidney damage and that NAC could completely block the F2-isoprostane increase caused by radiocontrast administration. We have shown that NAC not only increased creatinine clearance but also completely blocked the increase in F2-isoprostane levels. In addition, post-radiocontrast levels of -glutathione-S-transferase were significantly lower in the NAC group. The assessment of volume status by non-invasive techniques provides important information for clinical evaluation, but there is a lack of clearly defined standards for evaluating the findings. First, no single method has emerged as a gold standard, and a combination of these methods – including biochemical markers, bioimpedance analysis, inferior vena cava diameter determination and Doppler echocardiography – is needed frequently to compensate for their respective limitations [9]. Second, these techniques have been explored under conditions such as haemodialysis in end-stage renal disease (in contrast to our study population), in which maintaining volume status within an optimal range is critical. Third, analysis of the pulmonary vein Doppler spectrum, as described by Wu et al. [9] in haemodialysis patients, is limited by other factors, such as left ventricular systolic dysfunction, significant mitral regurgitation and atrial fibrillation [10]. We have developed an animal model of CIN in which we determined volume status by measuring the plasma volume and the volume of distribution of sodium. In this animal model, the rats were given free access to water and fed a low-salt diet. The rats received furosemide 1 week before radiocontrast administration [11]. We showed that these animals had normal plasma and blood volume and a normal volume of distribution of sodium. To measure the sodium space, we used 22Na and to measure blood volume the rats received 51Cr-tagged human albumin. In our patients, as in our animal model, a low-salt diet was given and the furosemide was discontinued prior to radiocontrast administration. Therefore, we believe that our study design created an effective vehicle by which to discuss the effect of NAC on proximal tubular injury, blocking the production of reactive oxidative species during radiocontrast examinations in homogeneous ambulatory CRF patients presenting a stable clinical condition.
Conflict of interest statement. None declared.
1 Heart Institute (InCor)2 Department of Nephrology University of São Paulo Brazil Email: trulu{at}usp.br
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